Depression is a common disease that causes significant morbidity and mortality in humans. There is currently a poor understanding regarding the underlying molecular, cellular or circuit mechanisms. Presently, therapeutic intervention is not well understood mechanistically and often unsuccessful. It is important to derive a mechanistic understand of depressive disorders so that effective treatment can be developed. In this project, based on considerable preliminary data, I propose a specific hypothesis regarding modification at a synapse in the brain reward circuit that may contribute to behavioral depression. Recent studies show that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, increase their activity when an animal fails to receive an expected positive reward, i.e. these neurons provide a 'disappointment' signal. LHb neurons project to and modulate dopamine-rich regions such as the ventral-tegmental area (VTA), which control reward-seeking behavior and participate in depressive disorders. Our preliminary results show that excitatory synapses onto VTA-projecting LHb neurons are about significantly stronger in rat models of depression compared to control animals. Furthermore, suppression of transmission onto LHb neurons relieves depressive-like behaviors in rodent models of depression. Thus, our central hypothesis is that aberrantly potentiated excitatory synapses onto LHb neurons contribute to depression. These neurons in the LHb thus provide an abnormally strong 'disappointment' signal, which leads to reduced reward-seeking behavior, a core feature of major depression. I will combine molecular, cellular, genetic and behavioral techniques to test this hypothesis in rodent models of depression. PUBLIC HEALTH RELEVANCE: Neurons in the lateral habenula provide 'disappointment' signals in the brain. We have found overactive excitation by synapses onto these neurons in rodent models of depression. Thus, reducing activity of these synapses may alleviate some forms of major depressive disorders.